1. Field of the Invention
The present invention relates to a process for the hydride transfer reduction rearrangement tricyclo [6.2.1.0.sup.2,6 ] undeca-2 (6)-ene.
The invention relates to a process for the synthesis of 4-homoisotwistane (tricyclo[5.3.1.0.sup.3,8 ]undecane), a known useful compound, having the formula (II): ##STR3## which comprises isomerizing tricyclo[6.2.1.0.sup.2,6 ]undeca-2(6)-ene having the formula (I): ##STR4## with concentrated sulfuric acid in the presence of a hydride source and simultaneously performing reduction with a hydride.
4-Homoisotwistane (II) is a compound recently synthesized for the first time by Krantz (Krantz, Chem. Commun., 1287 (1971) and J. Amer. Chem. Soc., 95, 5662 (1973)). It is a tricycloundecane having the same skeleton as that of seychellene, a kind of sesquiterpene.
We previously studied various functional reactions of the compound (II) and found that one of the derivatives of the compound (II), 3-amino-4-homoisotwistane, is a very effective antiviral agent.
The desired compound of formula (II) is very valuable as a starting compound for production of human medicines and animal medicines.
The process of the present invention can be performed very easily. Namely, the desired compound of formula (II) can be obtained by agitating the starting olefin of formula (I) at room temperature together with concentrated sulfuric acid and a hydrocarbon as a hydride source. After completion of the reaction, the hydrocarbon layer is separated and the hydrocarbon is removed by distillation or the like. Thus, the crude compound of formula (II) can be obtained in a yield of 35 to 40%, and the selectivity to the compound of formula (II) is as high as 92%. In acid-catalyzed isomerizations of tricycloundecanes, in general, if the reaction is not conducted until the final methyladamantane is formed and the reaction is stopped partway to completion, it seldom happens that a single product is predominantly obtained, but rather a complicated mixture of a number of tricycloundecane isomers is usually obtained (refer to our reports in J. Org. Chem., 40, 276, (1975), ibid, 1483 (1975), ibid, 40, 2929(1975). In view of the foregoing, it is quite surprising that in the process of the present invention, the compound of formula (II) can be obtained at such a high selectivity as 92%. This means that the process of the present invention is very valuable as a process for the synthesis of the compound of formula (II).
The concentrated sulfuric acid that is used in the process of the present invention has a concentration of 75 to 100%, preferably 90 to 98%. When the concentration is lower than 75%, isomerization is not advanced effectively, and when sulfuric acid having a concentration higher than 100% (fuming sulfuric acid) is used, an oxidation reaction takes place simultaneously and the yield is reduced. The amount of sulfuric acid employed is 1 to 1000 times, preferably 10 to 100 times, the amount of the starting formula (I) olefin (on a weight basis).
Any aliphatic or alicyclic hydrocarbon which has a boiling point in the range between 20 and 160.degree. C., preferably 30 and 100.degree. C., and is liquid under the reaction conditions can be effectively used as the hydrogen anion source. However, the use of hydrocarbons having an excessively high boiling point, such as above about 160.degree. C., must be avoided, because separation of the intended product by distilling off the hydrocarbon becomes difficult. For example, as acceptable hydride sources there can be mentioned n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, cyclooctane, methylcyclohexane, isooctane, petroleum ether and ligroin. The amount used of the hydride source has no substantial influence on the yield of the desired compound of formula (II), but it is generally preferred to use the hydride source in an amount of from 10 to 10.sup.3 times the amount of the starting formula (I) olefin (on a weight basis).
The reaction temperature is in the range of from -20.degree. to +100.degree. C., and temperatures approximating room temperature (20.degree. to 30.degree. C.) are especially preferred.
The starting compound of formula (I), tricyclo[6.2.1.0.sup.2,6 ]undeca-2(6)-ene, can be synthesized by dehydration isomerization of 5,6-exo-trimethylene-2-norbornylcarbinol (IV), 2-hydroxy- 6,7-exo-trimethylenebicyclo[3.2.1]octane (V), 3-endo-hydroxy-6,7-exo-trimethylenebicyclo[3.2.1]octane (VI) or 2-hydroxy-5,6-endo-trimethylenebicyclo[2.2.2]octane (VII), in the presence of phosphoric acid, or by isomerization of 6,7-exotrimethylenebicyclo[3.2.1]oct-2-ene (VIII), in the presence of phosphoric acid.
The starting carbinol (IV) is simply heated together with an excess amount of phosphoric acid. It is preferable to use a solvent in order to more intimately mix the carbinol (IV) with phosphoric acid. The solvent serves to suppress formation of polymer and thereby to increase the yield of the desired tricycloundecane.
The concentration of the used phosphoric acid may be 50 to 100%, preferably 70 to 90%. When a dilute phosphoric acid, i.e. the concentration thereof is less than 50%, is used, the dehydration reaction does not eventually take place. On the other hand, a phosphoric acid having a concentration of more than 100% promotes formation of polymers. The amount of phosphoric acid to be added may be 0.1 to 1000 times of the amount of the starting carbinol (IV), preferably 1 to 100 times. When the amount of the added phosphoric acid is less than 0.1 times of the amount of the carbinol, the reaction speed is extremely retarded.
Any solvents which are inactive to phosphoric acid and the compounds (IV) and (I) may be used in this synthesis, the most suitable solvents being aliphatic hydrocarbons which have no tertiary hydrogen atom, alicyclic hydrocarbons and aromatic hydrocarbons. A solvent having a tertiary hydrogen atom should not be used, because such a solvent delays the desired reaction or occasionally presents the reaction substantially. It is considered that the tertiary hydrogen atoms readily form hydrogen anions which tend to be transferred to carbocation from the carbinol (IV) or intermediate cations which are generated by isomerization of the carbocations thereby to retard or stop the isomerization reaction. Examples of usable solvents include n-pentane, n-hexane, n-heptane, cyclopentane, cyclohexane, benzene and toluene. The amount of the used solvent is not strictly restricted. However, the convenient amount of the used solvent is 1 to 1000 times, preferably 10 to 100 times, by weight of the amount of the starting carbinol (IV).
The reaction temperature may be 50 to 150.degree. C., preferably 80 to 110.degree. C.
5,6-Exo-trimethylene-2-norbonylcarbinol (IV) may be synthesized from 2-exo-chloro-5,6-exo-trimethylenenorbonane through a Grignard reaction or addition reaction to formaldehyde (Reference should be made to Japanese Patent Application No. 1974-62232 or Synth. Commun., 5(1975) both by the inventors).
The compound (V) may be, for instance, synthesized by hydrolyzing 3,4-dichloro-6,7-exo-trimethylenebicyclo[3.2.1]octo-2-ene (Reference should be made to the article by the inventors published in J. Org. Chem., 40, 276 (1975)) at its position 4 substituted with chlorine, and subjecting the obtained product successively to dechlorination and hydrogen addition methods.
The compound (IV) may be, for instance, synthesized by reducing 6,7-exo-trimethylenebicyclo[3.2.1]oct -3-ene (Reference should be made to the article by the inventors published in J. Org. Chem., 40, 276 (1975)) with the use of lithium aluminum hydride.
The compound (VII) may have either exo- or endo-hydroxyl group at position 2 thereof, and either one of which gives the desired compound (I) at the selectivity coefficient of 90% or more. 2-exo-hydroxy-epimer-hydroxyepimer of the compound (VII), i.e. 2-exo-hydroxy-5,6-endo-trimethylenebicyclo[2.2.2]octane (hereinbelow referred to as (VIIx)), may be synthesized by the hydroboration of endo-tricyclo[5.2.2.0.sup.2,6 ]undeca-8-ene (IX) as shown in the following reaction formula; and the 2-endohydroxy epimer of the compound (VII), i.e. 2-endo-hydroxy-5,6-endotrimethylenebicyclo[2.2.2]octane (hereinbelow referred to as (VIIn)), may be synthesized by reducing endo-tricyclo [5.2.2.0.sup.2,6 ]undeca-8-ene (X), which is obtained by Jones' oxidation of the compound (VIIx), with the use of lithium aliminum hydride. ##STR5##
The compound (VIII) is also a novel tricycloundecane and may be synthesized, for example, by dechlorinating 3,4-dichloro-6,7-exo-trimethylenebicyclo[3.2.1]octo-2-ene with the use of sodium and liquid ammonia.
The structure of the thus-obtained compound of the formula (I) can be confirmed by the fact that tricyclo[6.2.1.0.sup.2,6 ]undecane (III) obtained by hydrogenation of the thus-obtained formula (I) compound is in agreement with the standard substance (III) prepared according to the following scheme: